title: T cell–derived inducible nitric oxide synthase switches off Th17 cell differentiation.
abstract: RORγt is necessary for the generation of TH17 cells but the molecular mechanisms for the regulation of TH17 cells are still not fully understood. We show that activation of CD4⁺ T cells results in the expression of inducible nitric oxide synthase (iNOS). iNOS-deficient mice displayed enhanced T(H)17 cell differentiation but without major effects on either T(H)1 or T(H)2 cell lineages, whereas endothelial NOS (eNOS) or neuronal NOS (nNOS) mutant mice showed comparable T(H)17 cell differentiation compared with wild-type control mice. The addition of N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL), the iNOS inhibitor, significantly enhanced TH17 cell differentiation, and S-nitroso-N-acetylpenicillamine (SNAP), the NO donor, dosedependently reduced the percentage of IL-17–producing CD4⁺ T cells. NO mediates nitration of tyrosine residues in RORγt, leading to the suppression of RORγt-induced IL-17 promoter activation, indicating that NO regulates IL-17 expression at the transcriptional level. Finally, studies of an experimental model of colitis showed that iNOS deficiency results in more severe inflammation with an enhanced T(H)17 phenotype. These results suggest that NO derived from iNOS in activated T cells plays a negative role in the regulation of T(H)17 cell differentiation and highlight the importance of intrinsic programs for the control of T(H)17 immune responses.
authors.affiliation: Department of Medicine, Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.lastname: Jianjun Yang
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhang
authors.forename: Geming
authors.initials: G
authors.lastname: Lu
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Chen
authors.initials: C
authors.lastname: Zhu
authors.forename: Miao
authors.initials: M
authors.lastname: Cui
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Arnaboldi
authors.forename: Meng
authors.initials: M
authors.lastname: Tang
authors.forename: Monica
authors.initials: M
authors.lastname: Gupta
authors.forename: Chen-Feng
authors.initials: CF
authors.lastname: Qi
authors.forename: Padmini
authors.initials: P
authors.lastname: Jayaraman
authors.forename: Hongfa
authors.initials: H
authors.lastname: Zhu
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.forename: Shu-hsia
authors.initials: SH
authors.lastname: Chen
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.forename: Adrian T
authors.initials: AT
authors.lastname: Ting
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Sikora
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D003092:Colitis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058504:Th17 Cells / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology
chemical_list: D020381:Interleukin-17; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse